Opinion statement
Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, ...locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
Glioblastoma (GBM) is the most common primary brain tumor in adults and is universally lethal with a median survival of less than two years with standard therapy. RNA-based immunotherapies have ...significant potential to establish a durable treatment response for malignant brain tumors including GBM. RNA offers clear advantages over antigen-focused approaches but cannot often be directly administered due to biological instability. This review will focus on utilization of RNA dendritic cell vaccines and RNA nanoparticle therapies in the treatment of GBM. RNA-pulsed dendritic cell vaccines have been shown to be safe in a small phase I clinical trial and RNA-loaded nanoparticle vaccines will soon be underway in GBM patients (NCT04573140).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Laser interstitial thermal therapy (LITT) remains a promising advance in the treatment of primary central nervous system malignancies. As indications for its use continue to expand, ...there has been growing interest in its ability to induce prolonged blood brain barrier (BBB) permeability through hyperthermia, potentially increasing the effectiveness of current therapeutics including BBB-impermeant agents and immunotherapy platforms.
Methods
In this review, we highlight the mechanism of hyperthermic BBB disruption and LITT-induced immunogenic cell death in preclinical models and humans. Additionally, we summarize ongoing clinical trials evaluating a combination approach of LITT and immunotherapy, which will likely serve as the basis for future neuro-oncologic treatment paradigms.
Results
There is evidence to suggest a highly immunogenic response to laser interstitial thermal therapy through activation of both the innate and adaptive immune response. These mechanisms have been shown to potentiate standard methods of oncologic care. There are only a limited number of clinical trials are ongoing to evaluate the utility of LITT in combination with immunotherapy.
Conclusion
LITT continues to be studied as a possible technique to bridge the gap between exciting preclinical results and the limited successes seen in the field of neuro-oncology. Preliminary data suggests a substantial benefit for use of LITT as a combination therapy in several clinical trials. Further investigation is required to determine whether or not this treatment paradigm can translate into long-term durable results for primary intracranial malignancies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
To determine whether participation in a clinical trial was associated with improved survival in patients with glioblastoma (GBM).
Methods
Following IRB approval, patients were identified ...using CPT and ICD codes. Data was collected using retrospective review of electronic medical records. When necessary, death data was obtained from online obituaries. Inverse propensity score matching was utilized to transform the two cohorts to comparable sets. Survival was compared using Kaplan-Meyer curves and Wilcoxon Rank Sum Test.
Results
In this cohort of 365 patients, 89 were enrolled in a clinical trial and 276 were not. Patients enrolled in clinical trials had a significantly higher mean baseline KPS score, higher proportion of surgical resections, and were more likely to receive temozolomide treatment than patients not enrolled in a clinical trial. After inverse propensity score matching, patients enrolled in a clinical trial lived significantly longer than those not enrolled (28.8 vs 22.2 months, p = 0.005). A potential confounder of this study is that patients not in a clinical trial had significantly fewer visits with neuro-oncologists than patients enrolled in a clinical trial (7 ± 8 vs 12 ± 9, p < 0. 0001).
Conclusions
Clinical trials enroll patients with the most favorable prognostic features. Even when correcting for this bias, clinical trial enrollment is an independent predictor of increased survival regardless of treatment arm.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Opinion statement
Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for brain tumors including glioblastoma, other primary central nervous system (CNS) neoplasms, ...metastases, and radiation necrosis. LITT employs a fiber optic coupled laser delivery probe stabilized via stereotaxis to deliver thermal energy that induces coagulative necrosis in tumors to achieve effective cytoreduction. LITT complements surgical resection, radiation treatment, tumor treating fields, and systemic therapy, especially in patients who are high risk for surgical resection due to tumor location in eloquent regions or poor functional status. These factors must be balanced with the increased rate of cerebral edema post LITT compared to surgical resection. LITT has also been shown to induce transient disruption of the blood–brain barrier (BBB), especially in the peritumoral region, which allows for enhanced CNS delivery of anti-neoplastic agents, thus greatly expanding the armamentarium against brain tumors to include highly effective anti-neoplastic agents that have poor BBB penetration. In addition, hyperthermia-induced immunogenic cell death is another secondary side effect of LITT that opens up immunotherapy as an attractive adjuvant treatment for brain tumors. Numerous large studies have demonstrated the safety and efficacy of LITT against various CNS tumors and as the literature continues to grow on this novel technique so will its indications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
It is not known whether aspiration-specific catheters are necessary for successful mechanical thrombectomy, but if not, off-label use of more versatile catheters could offer significant cost savings ...over specialized aspiration catheters. The Syphontrak (Depuy Synthes, Raynham, MA, USA) support catheter is designed for introduction of devices into distal neurovasculature but is not specifically indicated for use in mechanical thrombectomy. We sought to compare our experience using this catheter to historical controls to show the non-inferiority of aspiration achieved.
Data were collected retrospectively on patients who underwent mechanical thrombectomy using the Syphontrak catheter for aspiration at our institution. Patient demographics, procedure characteristics, and outcome information was recorded. Results were compared to five landmark studies on mechanical thrombectomy: MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-IA.
There were 63 patients who underwent mechanical thrombectomy for anterior circulation ischemic stroke. Despite significantly older patients and greater time from symptom onset to groin puncture, Thrombolysis in Cerebral Infarction grade 2B or 3 reperfusion was achieved in significantly more patients than in MR CLEAN, ESCAPE, and REVASCAT. Development of symptomatic intracranial hemorrhage occurred in 6.4% of patients, which was not significantly different from MR CLEAN, ESCAPE, REVASCAT, and EXTEND-IA. Mortality was 19.1%, which was not significantly different from any of the trials.
These data support the off-label use of distal intracranial support catheters for this mechanical thrombectomy, which may result in significant cost savings over aspiration-specific catheters, especially in low-volume centers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Spinal cord gliomas are rare entities that often have limited surgical options. Immunotherapy has shown promise in intracranial gliomas with some research suggesting benefit for spinal cord gliomas. ...A focused review of immunotherapies that have been investigated in spinal cord gliomas was performed. The primary methods of immunotherapy investigated in spinal cord gliomas include immune checkpoint inhibitors, adoptive T-cell therapies, and vaccine strategies. There are innumerable challenges that must be overcome to effectively apply immunotherapeutic strategies to the spinal cord gliomas including low incidence, few antigenic targets, the blood spinal cord barrier, the immunosuppressive tumor microenvironment and neurotoxic treatment effects. Nonetheless, research has suggested ways to overcome these challenges and treatments have been effective in case reports for metastatic non-small cell lung cancer, melanoma, midline glioma and glioblastoma. Current therapies for spinal cord gliomas are markedly limited. Further research is needed to determine if the success of immunotherapy for intracranial gliomas can be effectively applied to these unique tumors.
Neurosurgery residency involves a complex structure with multiple hospitals, services, and clinic days, leading to challenges in creating equitable call schedules. Manually prepared scheduling ...systems are prone to biases, error, and perceived unfairness. To address these issues, we developed an automated scheduling system (Automated Optimization of Neurosurgery Scheduling System AONSS) to reduce biases, accommodate resident requests, and optimize call variation, ultimately enhancing the educational experience by promoting diverse junior-senior-attending relationships.
AONSS was developed and tailored to the University of Florida program, with inaugural use in 2021-2022 and mandatory implementation in the 2022-2023 academic year. 2019-2021 academic years were used as control. Residents were surveyed using Google Forms before and after implementation to assess its impact. Outcome measures included call and pairing variations, duty hours, as well as subjective factors such as satisfaction, fairness, and perceived biases.
Twenty-six residents (28%-39% female/year) were included in the study. AONSS was used for 6/13 blocks during the 2021-2022 academic year and 13/13 blocks for the 2022-2023 academic year. Overall call variation reduced by 70%. All other objective secondary measures have improved with AONSS. Weekly and monthly duty hours were reduced and less varied. Satisfaction scores improved from 21% reporting being somewhat satisfied or very satisfied to 90%. Fairness scores improved from 43% reporting being somewhat fair or very fair to 95%. Perception of gender bias decreased from 29% to 0%. No resident felt there was racial bias in either system.
Our newly developed automated scheduling system effectively reduces variation among calls in a complex neurosurgery residency, which, in return, was found to increase residents' satisfaction with their schedule, improve their perception of fairness with the schedule, and has completely removed the perception of sexual bias in a program that has a large percentage of females. In addition, it was found to be associated with decreased duty hours.
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